title: Structure-activity relationship study of novel iminothiadiazolo-pyrimidinone antimicrobial agents.
abstract: An iminothiadiazolo-pyrimidinone derivative, 0002-04-KK, harboring a furan moiety, acts as an antimicrobial agent with a minimum inhibitory concentration (MIC) against Staphylococcus aureus of 25 μg ml(-1). Several derivatives of 0002-04-KK were synthesized and among them 0026-59-KK, harboring a nitrofuran moiety, had the most potent antimicrobial activity with an MIC of 6 μg ml(-1). Both 0002-04-KK and 0026-59-KK inhibited the biosynthesis of DNA, RNA and proteins. Peptidoglycan biosynthesis was inhibited by 0026-59-KK, and slightly inhibited by 0002-04-KK. Derivative 0002-04-KK showed bactericidal activity in contrast to the bacteriostatic activity of 0002-04-KK. Derivative 0002-04-KK had less toxicity in silkworms (lethal dose fifty (LD50): >230 μg g(-1)) than 0002-04-KK (LD50: 100 μg g(-1)). The bactericidal activity against S. aureus was because of the nitrofuran moiety. These findings suggest that iminothiadiazolo-pyrimidinone compounds could be used as lead molecules to develop antimicrobial agents.
authors.affiliation: Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Atmika
authors.initials: A
authors.lastname: Paudel
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kaneko
authors.forename: Ayako
authors.initials: A
authors.lastname: Watanabe
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsunaga
authors.forename: Matsunaga
authors.initials: M
authors.lastname: Shigeki
authors.forename: Motomu
authors.initials: M
authors.lastname: Kanai
authors.forename: Kanai
authors.initials: K
authors.lastname: Motomu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamamoto
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Sekimizu
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000187:drug effects; D012831:Bombyx / Q000187:drug effects; D004269:DNA, Bacterial / Q000096:biosynthesis / Q000187:drug effects; D005658:Fungi / Q000187:drug effects*; D007928:Lethal Dose 50; D008826:Microbial Sensitivity Tests; D010457:Peptidoglycan / Q000096:biosynthesis / Q000187:drug effects; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D012329:RNA, Bacterial / Q000096:biosynthesis / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D018675:Toxicity Tests / Q000379:methods
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D010457:Peptidoglycan; D011744:Pyrimidinones; D012329:RNA, Bacterial